Alzheimer's disease (AD) is the most prevalent neurodegenerative disease and the leading cause of dementia among the elderly. The mechanisms underlying the onset and progression of neurodegeneration and cognitive decline are incompletely understood. A major breakthrough in our understanding of AD was the identification of gene mutations associated with rare familial AD (FAD) cases. Autosomal dominant mutations in the amyloid beta (A4) precursor protein (APP) and presenilin 1 and 2 (PSEN1/2) genes greatly accelerate the rate of cognitive decline leading to early-onset dementia (Bertram et al., 2010; Tanzi, 2012). The vast majority of AD cases, however, are late-onset forms (LOAD), which lack an obvious Mendelian inheritance pattern. LOAD has a strong genetic component and is likely caused by a combination of multiple risk alleles, each with modest and partially penetrant effects, and environmental factors (Bertram et al., 2010). Although apolipoprotein E ε4 (APOE ε4) remained for a long time the only confirmed genetic risk factor for LOAD, it accounts for only 10-20% of the LOAD risk, suggesting the existence of additional risk factors (Liu et al., 2013). Recently, genome-wide association studies (GWAS) performed on extended cohorts (thousands of individuals) led to the identification of additional confirmed genetic risk factors for AD: CD33 (Bertram et al., 2008; Hollingworth et al., 2011; Naj et al., 2011), CLU, BIN1, PICALM, CR1, CD2AP, EPHA1, ABCA7, MS4A4A/MS4A6E (Harold et al., 2009; Hollingworth et al., 2011; Lambert et al., 2009; Naj et al., 2011; Seshadri et al., 2010) and TREM2 (Guerreiro et al., 2013; Jonsson et al., 2013). Understanding the molecular and cellular activities of these novel genes, as well as their functional interactions, should greatly advance our understanding of AD.
The deposition of amyloid beta (Aβ)-containing plaques is a pathological hallmark of both FAD and LOAD. Aβ results from the amyloidogenic processing of APP, which is cleaved by the sequential action of β-secretase/BACE1 and γ-secretase/Presenilin (Querfurth and LaFerla, 2010). In FAD, both APP and PSEN1/2 mutations lead to enhanced amyloidogenic processing of APP and enhanced production of the toxic Aβ42 species (Querfurth and LaFerla, 2010). Less is known about the mechanisms of Aβ formation, self-assembly and clearance in LOAD. Interestingly, several genes linked to LOAD have been shown to impact Aβ generation, aggregation, or clearance (Bertram et al., 2010), suggesting that Aβ dysregulation is a central pathogenic mechanism in LOAD. A widely accepted model of AD pathogenesis is the “amyloid hypothesis” whereby increased production and self-assembly of Aβ toxic species initiates a series of progressive changes that ultimately lead to neurodegeneration (Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Tanzi and Bertram, 2005). In this hypothesis, persistent Aβ proteotoxic stress triggers the hyperphosphorylation and aggregation of the microtubule associated protein tau leading to neurofibrillary tangles, another pathological hallmark of AD (Tanzi and Bertram, 2005). Therefore, a better understanding of the mechanisms that regulate the generation and deposition, as well as clearance, of Aβ might improve the therapeutic approaches in AD.
Two single nucleotide polymorphisms (SNPs) in the CD33, rs3826656 (Bertram et al., 2008) and rs3865444 (Hollingworth et al., 2011; Naj et al., 2011), have been associated with LOAD. The 67 kDa type 1 transmembrane protein CD33 (Siglec-3) is a member of the sialic acid-binding immunoglobulin-like lectins (Siglecs) and is expressed in immune and hematopoietic cells. The Siglecs recognize sialic acid residues of glycoproteins and glycolipids, have one or more immunoreceptor tyrosine-based inhibition motifs (ITIMs) and mediate cell-cell interactions that inhibit or restrict immune responses (Crocker et al., 2012; Pillai et al., 2012). CD33 activity has been implicated in several processes such as: adhesion processes in immune or malignant cells, endocytosis, inhibition of cytokine release by monocytes and immune cell growth (Crocker et al., 2007; von Gunten and Bochner, 2008). To date, no functions have been described for CD33 in the brain.